Autoimmune diseases are a major problem in human health care. Some autoimmune diseases may be the result of an immunological process directed at one antigen or antigenic complex whereas in others the autoimmune reaction may involve many types of antigens that may be present in multiple organs.
The primary functional role of the immune system is to protect the individual against invading pathogens bearing foreign, that is non-self, antigens. In order to fulfil this function in a safe and effective manner, a mechanism is required to discriminate between foreign antigens and autoantigens derived from the individuals own body. Most individuals are in general tolerant to substances which occur in their own body.
Some individuals on the other hand fail to recognize their antigens as self and generate an immune response against endogenous substances, tissues, or components. Such an immune response causes great damage to the organs which contain these endogenous substances. The development of the associated autoimmune disease is in general very slow (a matter of years) and this hampers timely clinical diagnosis and treatment to a high degree. Diagnosis can generally only be made after appreciable damage has already been caused to the body.
The diagnosis of autoimmune diseases such as rheumatoid arthritis (RA) is most difficult in early disease or when relatively few joints are involved and unfortunately diagnosis is usually delayed several months after the onset of symptoms. Distinguishing e.g. rheumatoid arthritis from other causes of chronic inflammatory arthritis or transient synovitis syndromes at this point is difficult. Patients with a persistent undifferentiated polyarthritis syndrome are frequently seen and differentiation from rheumatoid arthritis may initially be difficult. Many patients will present with signs and symptoms of inflammatory arthritis but do not have rheumatoid arthritis.
The chances of individuals to develop an autoimmune disease are closely linked to their genetic backgrounds: genes encoding major histocompatibility complex (MHC) class II molecules that present (auto)antigens to responding T cells which recognize MHC-peptide complexes show a strong genetic linkage to disease susceptibility. In early disease the pathogenesis is thought to be T cell mediated. T cells recognize specific major histocompatibility complex molecules combined with antigenic peptide by virtue of the T-cell receptor (TCR). The signal generated by the MHC/peptide/TCR complex leads to T cell activation. This trimolecular complex is a key element in the general immune response and in autoimmunity. It is currently believed that the presentation of MHC-bound processed autoantigens to the TCR of CD4+ T cells is involved in the pathogenesis of many autoimmune diseases.
One of the candidate autoantigens identified in rheumatoid arthritis is human cartilage glycoprotein-39 (HC gp-39) (Verheijden et al., 1997, Arthritis and Rheum., 40:1115-1125). Immunisation of BALB/c mice with this protein resulted in the development of a chronic, relapsing arthritis. Intranasal administration of the protein prior to this immunization resulted in: i) complete abrogation of DTH responses, and ii) protection from or delayed onset of the disease. Furthermore, HC gp-39 could reduce the is incidence and severity of collagen type II induced arthritis in DBA/1 mice using a semi-therapeutic regime (Joosten et al., 2000, Arthritis Rheum. 43:645-655).
Several peptides of HC gp-39 were identified as potentially self-reactive. At least four of these peptides (103-116, 259-271, 263-275 and 326-338) are recognized by T cells of RA patients. Interestingly, HC gp-39263-275 was more prominently recognized in RA patients than in healthy controls, suggesting a role for this T-cell epitope in initiation or maintenance of rheumatoid arthritis. This peptide is therefore of interest for therapeutic and diagnostic purposes in RA. For therapeutic purposes, the peptide or a modification can be used for nasal tolerization. Furthermore, the peptide complexed with DRB1*0401 can be used for intravenous tolerization.
The peptide complexed to a MHC molecule can be exploited for diagnostic purposes. The conventional way to detect specific MHC-peptide complexes relies on the activation of T cells bearing relevant TCR. However, such functional assays cannot be used to identify TCR-ligand-bearing APC in tissue sections.
According to the present invention antibodies have been generated having specificity for a MHC-peptide complex associated with an autoimmune disease, preferably rheumatoid arthritis. Most preferred is a peptide in the complex derived from HC gp-39.
MHC-peptide complexes are syndrome-specific, i.e. the disease is characterized by the occurrence of such specific complexes of MHC and autoantigen.